Injectable in situ forming hydrogel systems provide an attractive alternative to microspheres or implants as parenteral depot systems. Proteins represent a group of the most effective, natural and the fastest growing medicines for treatment of nearly 150 indications including various severe chronic conditions such as cancer, diabetes, hepatitis, leukemia and rheumatoid arthritis. A critical problem in protein therapy is that most protein drugs are currently administered by frequent injections due to their tissue impermeability and short in vivo life. The sustained release of proteins via in situ forming hydrogel systems has a number of advantages, such as ease of administration (less invasive compared to implants), simple fabrication method, ease of manufacturing, low cost of goods and the like. Also, sustained local release of proteins and other pharmaceutical agents provides improving bioavailability, reducing risk of systemic side effects, improving patient compliance and allowing the highest concentration of drug at disease site. One of the challenging issues in local drug delivery is the risk of infection, discomfort, and pain associated with frequent injections. Therefore, the number of injections per year should be reduced to a minimum.
PEG-based hydrogels have been prepared using Michael-type addition reaction such as, PEG-thiol or PEG-amine reacting with PEG-activated ester (NHS) or PEG-acrylate. These systems are typically nonabsorbable, the gelation times are not fast enough, and the reactions can result in unwanted small molecules as a secondary by product. Furthermore, the PEG-NHS compound may react with protein drugs due to the activated ester that reacts with amino groups to form an amide bond. Similarly, PEG-based hydogels have been prepared using 4-armPEG-vinylsulfone and linear PEG-estersulfhydryl. However, such PEG-based hydrogels absorb too quickly, within 5 days (S. Zustiak and J. Leach, “Hydrolytically Degradable Poly(Ethylene Glycol) Hydrogel Scaffolds with Tunable Degradation and Mechanical Properties”, Biomacromolecules 2010, 11, 1348-1357), for example.
Therefore there is a need for an improved, fast forming PEG-based hydrodgel for a sustained release composition for proteins which is absorbable and yet can exhibit sustained release over a prolonged periods of time, for example greater than or equal to one month.